A murine model has been developed of graft-versus-host disease (GVHD) due to minor histocompatibility antigens (minor HA) in two strain combinations selected for H-2 identity and for mutual nonreactivity in MLC: C57BL/6-LP (H-2b combination) and B10.D2/nSn-BALB/c (H-2d combination).This model possesses many characteristics in common with human GVHD, including acute and chronic forms. This model has been used to systematically study the immune mechanisms which produce GVHD in response to minor HA. The histopathology of GVH skin disease has been described in a collaborative study with Dr. Richard Sontheimer, Dept. of Dermatology, Dallas, TX. The presence of cytolytic T lymphocytes (CTL) in mice with transplants does not correlate with GVH and may not represent the significant effector mechanism of GVH. A new assay of the proliferative response to minor HA has been developed to study the role of non-CTL in the pathogenesis of minor HA-GVHD. Congenic strains of mice developed between C57BL/10, LP and 129 mice have been used to demonstrate that multiple minor H antigenic differences must exist between donor and recipient strains for GVH to develop. Studies are in progress to evaluate the immunoregulation of cellular responses to minor HA in mice with transplants.